PROJECT SUMMARY/ABSTRACT Depression often emerges during adolescence, the transition between childhood and young adulthood, and is twice as common in girls than boys. Clinical depression and sub-threshold depressive symptoms in adolescence are prevalent and associated with functional impairment and increased risk for suicide. It is not clearly understood why girls are more vulnerable to depression. Vulnerability may involve biological, psychological, social, and neurodevelopmental factors, including altered development of the autonomic nervous system (ANS), a key system controlling most of our bodily functions and mediating our interactions with environmental challenges; abnormal functioning of the ANS is implicated in the etiology of depression. The ANS undergoes profound changes across adolescence with cross-sectional data suggesting sex differences in ANS development, toward an overall more unfavorable profile (lower vagal-related ANS function) in girls. Whether this unfavorable ANS profile is a pathway to vulnerability for depression symptoms in girls is unknown and requires longitudinal data. Here, we aim to address this gap, using supplemental funds to analyze sex differences in ANS trajectories across 4 years in relation to depression symptoms using data already collected during sleep in adolescents (aged 12-21 years old at baseline, n=150) in the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA) cohort. NCANDA is an on-going (2012-2022) multisite study examining the effects of alcohol use on the developing brain in a community sample of healthy youth at baseline. The unique advantage of the NCANDA data is the ability to analyze HRV within prolonged periods of stable sleep, free from wake-related confounders, allowing the assessment of basal ANS function and ANS reactivity to specific phasic sleep events. Aim 1: Investigate sex differences in ANS maturation across four years in young people (baseline, 1-, 2-, and 3-year follow-ups), considering relevant covariates including pubertal stage, physical activity, and sex hormones. Aim 2: Investigate whether ANS trajectories predict depressive symptoms in adolescents. The proposed analysis addresses two goals of the NIH Strategic Plan for Women's Health Research (Goal 1 to increase sex differences research in basic science studies, and Goal 2 to actualize personalized prevention, diagnostics, and therapeutics for girls and women) by addressing objectives: assess sex differences in neurobehavioral mechanisms of psychopathology, and conduct developmental research to understand the role of hormones and hormonal changes on conditions affecting women and girls throughout the life span.